The invention relates generally to nuclear magnetic resonance (NMR) magnetic resonance imaging (MRI), and more particularly to signal enhancement and detection.
Nuclear magnetic resonance (NMR) is a technique for obtaining information about atoms and the molecules they form. NMR operates on atoms having nuclei in which at least one proton or neutron is unpaired. This imbalance causes these nuclei to spin on an axis like miniature tops and gives rise to a magnetic moment, i.e. the nuclei behave like magnets with north and south poles.
When exposed to an external magnetic field, these spinning magnets attempt to align their axes along the lines of magnetic force. The alignment is not exact, however, resulting in a wobbly rotation (precession) about the force lines that is unique for each type of nuclei. If, while exposed to the magnetic field, the nuclei are bombarded with radio (RF) waves, they will absorb and re-emit energy at a specific frequency according to their rate of rotation. This resonating frequency therefore becomes a signature signal by which the nuclei can be identified.
When nuclei absorb the energy of an incoming radio wave, they are knocked out of alignment with the external magnetic field lines. As they subsequently lose this energy, the nuclei come back into alignment. The rate at which resonating nuclei realign themselves with magnetic field lines provides detailed information on their position and motion with respect to neighboring nuclei. This provides a noninvasive technique to study the structural, dynamic, and spatial relationships of atoms in a sample of molecules.
NMR has two basic subsets--spectroscopy and imaging. In NMR spectroscopy, the frequency of the incoming radio wave is varied, and all of the different frequencies absorbed and emitted by the nuclei are measured to obtain a resonance spectrum. This NMR spectrum reveals the molecular makeup of the material down to the respective positions and motions of the constituent atoms.
In magnetic resonance imaging (MRI), the frequency of the incoming radio wave is kept constant, but the strength of the external magnetic field is varied. The resulting signal corresponds to the total number of spinning nuclei present in any part of the sample, i.e. the atomic density of the sample at that point. Information obtained from an array of points can be translated by computer into a recognizable image.
A major problem with NMR is low signal level, which makes the signal difficult to detect and to interpret. The problem is inherent and occurs because the axes will point in either the "up" or "down" (i.e. parallel or antiparallel) direction when the spinning atomic nuclei align themselves with the magnetic field lines. The NMR signals from nuclei pointing in opposite directions cancel one another out. If a sample contained an equal number of nuclei with spins pointing in opposite directions, no NMR/MRI signal would be produced. The degree of spin polarization, i.e. spin axes pointing in a single direction, is very low; the natural population difference between up and down nuclear spins in NMR magnets is usually no more than one in 100,000 at room temperature. A number of techniques have been developed to increase the NMR signal, including multiple quantum NMR, zero field NMR, double rotation NMR, and dynamic angle spinning NMR.
The Spin-Polarization-Induced Nuclear Overhauser Effect (SPINOE) is a technique in which xenon (or other inert) gas is specially treated (hyperpolarized) so that it can amplify the NMR signals from any atomic nuclei with which it makes contact. Xenon is chemically unreactive with other atoms, and readily dissolves in solutions. Xenon atoms show a small degree of natural polarization in their spin, but zapping them with a beam of polarized laser light creates a hyperpolarized effect in which most of the spins point in the same direction. The transfer of polarization from photons to the spins of atomic nuclei is done by the process of optical pumping.
The hyperpolarized xenon nuclei emit a strong NMR signal. When hyperpolarized xenon gas is bubbled into a solution, polarization from xenon nuclei is transferred to the nuclei of atoms in the solution, amplifying their NMR/MRI signals. Every area in a sample accessed by hyperpolarized xenon is going to light up to some extent with an enhanced NMR signal. Through SPINOE NMR, polarization can be transferred from a gas to nuclei on a solid surface so that the surface can be distinguished from the bulk.
A further advantage of hyperpolarized xenon for medical imaging is the aversion of xenon to water so that the hyperpolarized xenon nuclei will concentrate around water free sites, e.g. on a protein, and enhance the resulting NMR/MRI signal. One potential problem with using laser polarized xenon in medical applications is efficiently delivering the xenon while maintaining the large polarization acquired during optical pumping. This has been accomplished by predissolving laser polarized xenon in a biologically compatible solution. The polarized xenon gas is frozen at liquid nitrogen temperature, sublimated, put into a solution, and shaken until dissolved. Following this treatment, loss of polarization during injection became insignificant. Suitable solutions include saline and blood substitutes such as perfluorocarbon emulsions.
The use of hyperpolarized inert gases to enhance NMR/MRI signals is described in U.S. patent application Ser. No. 08/825,475 filed Mar. 28, 1997, which is herein incorporated by reference.
Superconducting Quantum Interference Devices (SQUIDs) are sensitive detectors of magnetic fields based on the quantum mechanical Josephson effect. SQUIDs are based on superconductors, whose resistance drops to zero when cooled to a critical temperature Tc. A SQUID is formed by separating its superconducting material with a very thin insulating barrier through which electron pairs can tunnel. This combination of superconducting material and insulating barrier forms a Josephson junction, i.e. two superconductors joined by a weak link. The SQUID consists of a superconducting ring or square interrupted in two spots by Josephson junction. When sufficient electrical current is applied to the SQUID, a voltage is generated across its body. In the presence of a magnetic field, this voltage will change as the strength of the field changes. Thus the SQUID turns a change in a magnetic field, which is more difficult to measure, into a change in voltage, which is very easy to measure. A high Tc low noise SQUID is described in U.S. Pat. No. 6,023,161 filed Feb. 27, 1998, which is herein incorported by reference.
For application purposes, SQUIDs are almost always coupled to auxiliary components. To form a magnetometer, a SQUID is connected to a flux transformer, a device consisting of a relatively large loop of superconducting material and a much smaller multiturn coil. Since the large loop picks up a magnetic field over a much greater area, the sensitivity of the SQUID to changes in magnetic field strength is boosted manyfold.
Originally SQUIDs were made with low Tc superconductors, e.g. niobium (Tc=9.5K), which required cooling with liquid helium. More recently, high Tc SQUIDs have been made, using high Tc ceramic oxide superconducting materials, e.g. yttrium barium copper oxide (YBCO) materials (Tc=93K), which only require cooling with liquid nitrogen, which is much less expensive and easier to work with than liquid helium.
Low transition temperature SQUIDs have been used experimentally to detect NMR and nuclear quadrupole resonance (NQR) signals, e.g. Dinh M. TonThat et al., "Direct current superconducting quantum interference device spectrometer for pulsed nuclear magnetic resonance and nuclear quadrupole resonance at frequencies up to 5 MHz," Rev. Sci. Instr. 67, 2890 (1996). Low Tc SQUIDs have been used to image polarized helium and xenon at relatively low fields, e.g. M.P. Augustine et al., "Low field magnetic resonance images of polarized noble gases obtained with a dc superconducting quantum interference device," Appl. Phys. Lett. 72 (15), 1908 (1998). The feasibility of using a high Tc SQUID to detect NMR signals has been demonstrated, S. Kumar et al., "Nuclear magnetic resonance using using a high temperature superconducting quantum interference device," Appl. Phys. Lett. 70 (8), 1037 (1997).
The NMR effect is produced by a spin magnetic moment on nuclei in a sample. A magnetic field causes the spin magnetic moments to precess around the field at the Larmor frequency .omega. which is proportional to the magnetic field.
In low field NMR (typically .ltoreq.10 mT) the spin precesses at correspondingly low frequencies, typically below 500 kHz, around the field direction. In conventional NMR, in which a resonant circuit is used to detect the precessing magnetization, the induced voltage signal V is proportional to the spin magnetization M and its rate of change (frequency) .omega.. Since M is also proportional to the frequency .omega., V scales with .omega..sup.2. As a result it is difficult to detect NMR signals at low fields with a conventional Faraday detector. In contrast, SQUIDs can be used to measure magnetic flux directly, resulting in much higher signal to noise (S/N) ratio at low frequencies. However, it has not been heretofore possible to detect NMR signals from small samples (about 1 ml), at temperatures as high as room temperature, and in magnetic fields as low as 0.1 mT.